It has been argued that widespread extinctions of top predators have changed terrestrial ecosystem structures through mesopredator release, where increased abundances of medium-sized predators have detrimental effects on prey communities. This top-down concept has received much attention within conservation biology, but few studies have demonstrated the phenomenon. The concept has been criticized since alternative explanations involving bottom-up impacts from bioclimatic effects on ecosystem productivity and from anthropogenic habitat change are rarely considered. We analyse the response of a mesopredator (the red fox) to declines in top predators (wolf and Eurasian lynx) and agricultural expansion over 90 years in Sweden, taking bioclimatic effects into account. We show a top-down mesopredator release effect, but ecosystem productivity determined its strength. The impacts of agricultural activity were mediated by their effects on top predator populations. Thus, both top-down and bottom-up processes need to be understood for effective preservation of biodiversity in anthropogenically transformed ecosystems.